Memory T cells are heterogeneous in terms of their phenotype and functional properties. We investigated the molecular profiles of human CD8 naive central memory (T CM), effector memory (T EM), and effector memory RA (T EMRA) T cells using gene expression microarrays and phospho-protein-specific intracellular flow cytometry. We demonstrate that T CM have a gene expression and cytokine signaling signature that lies between that of naive and T EM or T EMRA cells, whereas T EM and T EMRA are closely related. Our data define the molecular basis for the different functional properties of central and effector memory subsets. We show that T EM and T EMRA cells strongly express genes with known importance in CD8 T cell effector function. In contrast, T CM are characterized by high basal and cytokine-induced STAT5 phosphorylation, reflecting their capacity for self-renewal. Altogether, our results distinguish T CM and T EM/T EMRA at the molecular level and are consistent with the concept that T CM represent memory stem cells.